PENGANTAR TOKSIKOLOGI

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1 PENGANTAR TOKSIKOLOGI
Dr. H.Achmad Basori, MS Profesor Farmakologi Departemen Farmakologi Dan Terapi Fakultas Kedokteran UA

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6 Pharmacology : Dogma and Reason
Ancient Beginnings - Religious /magical Hippocrates ( ~ 460 BC) - Observation / experience Paracelcus ( 1439 – 1541) - Applyng chemistry to medicine 1600 – 1900 Materia Medica - Experimental Physiology, Cause of Disease - Isolation of Active Principles, Synthetic Chemistry 1900 ~ Modern Era - Efficacy and Safety - Clinical Trial

7 Ancient Beginnings - Religious /magical
The Ebers papyrus, written in Egypt in the 16th century B.C., lists the extensive pharmacopia of that civilization. Included in this are: beer, turpentine, myrrh, , juniperberries., poppy, lead, salt and crushed precious stones. Also included were products derived from animals, including lizard's blood, swine teeth, goose grease, ass hooves and the excreta from various animals. The effects of many of these drugs on patients of antiquity can only be imagined.

8 Hippocrates ( ~ 460 BC) - Observation / experience (empiric- primitive)

9 Paracelcus ( 1439 – 1541)  Pharmacon or Toxicon ?
- Applyng chemistry to medicine(empiric analytic)

10 "The dose makes the poison.“
Swiss physician Paracelsus ( ) credited with being “the father of modern pharmacology/ toxicology.” “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison from a remedy.” He determined that specific chemicals were actually responsible for the toxicity of a plant or animal poison.  Paracelsus is often quoted for his statement:  "All substances are poisons; there is none which is not a poison.  The right dose differentiates a poison and a remedy." "The dose makes the poison.“

11 OBAT = PISAU BERMUKA DUA
MANFAAT : satu bahan bisa mendatangkan satu atau lebih efek yg menguntungkan yg digunakan utk medikasi MUDARAT : satu bahan mempunyai beberapa macam efek yg merugikan dg berbagai tingkatan dari yg ringan berat s/d fatal (side effect & adverse effect) Besar kecilnya manfaat/mudarat yg muncul dalam pengobatan tergantung dari dosis. Drug (Pharmacon) Batas kadar terapi Dalam darah Cyclosporine ng/ml Phenytoin 10 – 20 mg/ml Gentamicin 2 – 4 mg/ml Theophylline Digoxin 1 – 2 ng/ml Obat = racun Obat ”aman” bila digunakan dengan kaidah/hukum Farmakologi (Klinik)

12 1600 – 1900 Materia Medica - Experimental Physiology, Cause of Disease - Isolation of Active Principles, Synthetic Chemistry

13 1900 ~ Modern Era - Efficacy and Safety - Modern Toxicology studies
- Clinical Trial

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15 Isoproterenol (Isoprel) Inhaler
Bronchodilator Cardiac Arrest Isoproterenol  Pure beta receptor agonist ( non- selective) Tidak mempunyai efek thd alpha-receptor

16 DRUG DISCOVERY & DEVELOPMENT PROCESSES
Overall cost per marketed compound = $ 1 – 1.2 billion time-scale = years Total patent lifetime = ~30 years DRUG DISCOVERY EARLY DEVELOPMENT CLINICAL DEVELOPMENT Phase I Phase II Phase III Phase IV Target selection Lead-finding Lead optimisation Pharmacological profiling Pharmacokinetics Short-term Toxicology Formulation Synthesis scale-up Pharmacokinetics,tolerability, side effects in healthy volunteers Small-scale trials in patients to assess efficacy & dosage Large-scale controlled trials To develop a drug is a costly process. Only 10-20% of all potential drugs reach the level of early development, 3-5% clinical development and 1-2% finally reach the market. Post-marketing surveillance 2-5 years (10-20%) 1 year (3-5%) 5-7 years (1-2%) Drug candidate Development compound Compound approved for marketing Chao Han dkk,2010 Rick et al,2010

17 Pharmakon + Logos? Toxikon + Logos? What is Toxicology Pharmacology :
Old Greek = poison Modern Greek = Drug Pharmacology : Pharmakon + Logos? Toxikon Logos? Toxicology :

18 Perkembangan Ilmu Toksikologi
Pharmacology (Pharmacon+Logos): Ilmu tentang senyawa (obat) yang digunakan untuk mencegah, mendiagnosa, dan mengobati penyakit Toxicology (Toxicon + Logos) : Suatu cabang dari ilmu farmakologi yang mempelajari efek yang tidak dikehendaki dari senyawa kimia pada sistem biologi (Undesirable) (ASPET,2000) The Science of Poisons (ToxiCology) The study of toxic effects of chemicals on living systems. Study oh how natural or man made poisons cause undesirable effects in living organism PATHOLOGY: Study of structural and functional changes in cells, tissues and organs after toxic exposure

19 Efek Bahan / Obat Desirable Diharapkan (Therapeutic) Undesirable
Tidak Diharapkan Non-deleterious (Side effects) Deleterious (Toxic effects)

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21 DEFINISI - Toxicosis : disease state that results from exposure to a poison.

22 Toxicon Poisonous substances are produced by plants, animals, or bacteria. Phytotoxins Zootoxins Bacteriotoxins Toxicant - the specific poisonous chemical. Xenobiotic - man-made substance and/or produced by but not normally found in the body.

23 Xenobiotics ( Xenos, Foreign Chemical)
Xenobiotics may be naturally occurring chemicals produced by plants, microorganisms, or animals (including humans). Xenobiotics may also be synthetic chemicals produced by humans. Poisons are xenobiotics, but not all xenobiotics are poisonous. Xenobiotic are substances which normally is not needed by our body

24 History Swiss physician Paracelsus (1493-1541) credited with being
“the father of modern toxicology.” “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison from a remedy.” He determined that specific chemicals were actually responsible for the toxicity of a plant or animal poison.  Paracelsus is often quoted for his statement:  "All substances are poisons; there is none which is not a poison.  The right dose differentiates a poison and a remedy." "The dose makes the poison.“

25 Paracetamol  dosis terapi : analgesik antipiretik  dosis tinggi  kanker hati Viagra  dosis terapi : erectogenic  dosis tinggi : permanent blindness Morphine  dosis terapi : analgesik kuat  dosis tinggi : depresi pernafasan Air (H2O) :  1 gelas : tdk apa apa  1 galon : lambung pecah Gula :  jumlah kecil : pemanis  jumlah besar : hyperglycemia  diabet  Coma

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27 Toxic Therapeutic Theophrastus von Hohenheim (Paracelcus,1493 – 1541)
All things are poison, nothing is without poison Toxic Minimum Toxic Concentration Therapeutic Minimum Effective Concentration Ineffective

28 Pharmacon atau Toxicon = Drug Toxicity
Batas kadar terapi Dalam darah Cyclosporine ng/ml Salicylic acid > 200 mg/ml Phenytoin 10 – 20 mg/ml Gentamicin 2 – 4 mg/ml Theophylline Digoxin 1 – 2 ng/ml

29 EFEK FARMAKOLOGI HIGH Coma Hypnosis LOW Dosis (mg/kg BB) DEATH GENERAL
ANESTHESIA Confusion, Delirium, Ataxia EFEK FARMAKOLOGI Hypnosis SEDATIVE EFFECTS Drowsiness/ decrease reaction time ANTI- CONVULSANT EFFECTS ANXIOLYTIC EFFECTS Dosis (mg/kg BB) LOW Phenobarbital (Luminal)  5x dosis hipnotik  depresi nafas

30 Toxicity: Derajad kemampuan suatu senyawa bersifat racun dan menyebabkan kerusakan Toxicity tergantung : dosis, lama pemaparan, rute pemaparan,bentuk & struktur senyawa, faktor individu Toxic : Efek racun atau mematikan terhadap tubuh melalui inhalasi, oral, kontak langsung dgn bhn kimia Toxicant : tiap bahan kimia yang dpt melukai atau membunuh manusia, hewan, tanaman = Poison. Toxicant banyak dikaitkan dgn bahan yg dihasilkan dari produk hasil aktifitas manusia.Mis, Dioxin suatu bahan by produk pada proses khlrinasi bhn kimia.Arsenic merupakan kontaminan air atau hasil limbah industri Toxin : Senyawa toksik hasil alam. Merupakan senyawa racun dari hewan, tanaman (bacterio toxin, Zootoxin, Phytotoxin Toxicosis : Suatu penyakit yang terjadi akibat terpapar pada suatu toxicant

31 Itai Itai Disease Penyebab terpapar cadmium secara khronik (Di daerah pertambangan , Jepang). Akumulasi logam berat di air minum  gagal ginjal, perlunaan tulang, lumbago, arthralgia, dan full-body muscle spasm. Diiringi rasa sakit hebat, patah tulang lengan/kaki, tubuh menjadi pendek 56 orang dila[porkan meninggal.

32 Klasifikasi Toxicant / Poison
Berdasarkan target organ : hepatotoxican,nephrotoxicant,cardiotoxicant, dll Berdasarkan penggunaannya: pesticide,solvent,food additive,dll) Berdasarkan asal bahan: animal toxins, plant toxins Berdasarkan efek: mutation,cancer,liver injury,dll Berdasarkan siFat fisik: gas, dust, liquid Berdasarkan reaktifitas kimia labeling:explosives,flammable,oxidizer,dll) Bedasarkan struktur kimia : aromatic amine,halogenated hydrocarbon,dll Berdasarkan potensi toxicant : extremely toxic,very toxic, super toxic, dll Berdasarkan mekanisme kerja : sulhydriyl inhibitor,methoglobin producer,dll)

33 Toxicant ( Poison = Xenobiotics)
Obat-Obatan (Psikotropik=Sedatives-hypnotics,Tranquillizer,Antidepressant,cardiovascular,Hormon,Alcohol,street drugs,Obat obat OTC,dll) Cleaning/polishing agent,hydrocarbon, paint,pestisides,corrosive,ll) Foods,Botulinum, TTX,Insect bites,dll) Animal toxin (TTX, insect bites,dll) Gas (CO,NO,Freon,dll) Industrial product (heavy metals): As, Pb, Hg,Cd,Chrom,Ba,Li,Fe,dll Cosmetics Venome Dan lain lainnya

34 TOXICOLOGY Basic Science Medical Toxicology : - Biochemical Toxicology
Biology, Biochemistry,Pathology, Physiology, Genetic, Pharmacology TOXICOLOGY Medical Toxicology : - Biochemical Toxicology - Analytical Toxicology - Cellular Toxicology Molecular Toxicology - Clinical Toxicology - Forensic Toxicology -Food Toxicology - Ecotoxicology - Industrial Toxicology -Enviromental Toxicology -Occupational Toxicology -Developmental and reproductive Toxicology -Regulatory Toxicology -Mechanistic Toxicology - Descriptive Toxicology

35 Area toksikologi khusus yang penting utk kedokteran :
Forensic toxicology  kombinasi kimia analitik dan toksikologi dasar yang memperhatikan aspek medikolegal Clinical toxicology  fokus pada penyakit yang disebabkan atau secara unik berhubungan dengan substansi toksik Occupational toxicology  Toksikologi di tempat kerja - berhub dg bhn kimia disekitar tempat kerja - terutama identifikasi “agent” - kondisi tempat kerja aman, absorbsi bahan kimia berlebih dapat dicegah - guideline  konsentrasi bahan kimia di udara yang pasti aman (establish)  ada daftar bahan kimia yg direkomendasikan memenuhi threshold limit values (TLVs). Guideline selalu di evaluasi  new information

36 TOKSIKOLOGI LINGKUNGAN
- berhubungan dg dampak kimia sbg polutan di lingkungan organisme hidup  udara, tanah, air, dll - target utama manusia, spesias lain target biologik potensial Polusi udara  produk industri pengembangan teknologi peningkatan urbanisasi Polusi tanah dan air  pestisida Pengolahan makanan  residu bahan kimia pada produk makanan

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38 Ukrainian president Viktor Yushchenko, after alleged poisoning with dioxin, and, possibly endotoxin, prior to the 2004 elections.

39 MOLECULES OF DEATH 1. 1.Aflatoxin 2. Botulinus Toxin
3. Carbon Monoxide – Ther Silent Killer 4. Domoic Acid 5. Ecstacy 6. Heroin 7.Hydrofluoric Acid 8.Hydrogen Sulphide 9.Lead : An old and Modern Poison 10.Mercury 11.Mushroom Toxin 12.Nerve Gases 13.Nicotine and Tobacco Alkaloid 14.Paracetamol (Acetominophen) 15.Paraquat and Diquat 16.Phosphorus 17.Radon 18.Ricin 19.Snake Toxin 20.Spider Toxin 21.Strychnine 22.Tetrodotoxin 23.Thallium 24.Arsen 25.Cyanide 1.

40 Keracunan bahan kimia di IRD RSUD Dr
Keracunan bahan kimia di IRD RSUD Dr. Soetomo Surabaya dalam 5 tahun terakhir (Hernomo, 2001) Nama Bahan 1. Pestis. 128 (32.82%) 150 (29.30%) 84 (22.11%) 75 (22.52%) 78 (31.84%) 2. Ob. Farm. 120 (30.77%) 227 (44.34%) 159 (41.84%) 137 (41.14%) 81 (33.06%) 3. Minyak 60 (15.38%) 45 (8.79%) 29 (7.63%) 38 (11.41%) 32 (13.06%) 4. Makanan 13 (3.33%) 35 (6.84%) 39 (10.26%) 23 (6.91%) 8 (3.27%) 5. Alkohol 24 (6.15%) 14 (2.73%) 22 (5.79%) 30 (9.01%) 20 (8.16%) 6. Rmh tng 8 (2.05%) 11 (2.15%) 7 (1.84%) 5 (1.50%) 3 (1.22%) 7. Gas 2 (0.51%) 4 (0.78%) 2 (0.53%) 0 (0%) 0 (0%) 8. Ob. Trad. 11 (2.82%) 3 (0.59%) 6 (1.58%) 12 (3.60%) 2 (0.82%) 9. Korosif 18 (4.62%) 14 (2.73%) 10 (2.63%) 11 (3.30%) 5 (2.04%) 10. Lain-lain 2 (0.60%) 0 (0%) 0 (0%) 0 (0%) 3 (1.22%) 11. Tak diket. 6 (1.54%) 16 (4.21%) 0 (0%) 0 (0%) 13 (5.31%) Total 390 (100%) 512 (100%) 380 (100%) 333 (100%) 245 (100%)

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42 TOXICOKINETICS AND TOXICODYNAMIC
Bagaimana toksikan memasuki tubuh ? Bagaimana nasib toksikan didlm tubuh ? Bagaimana efek tubuh terhadap terhadap toxicant ? Bagaimana efek toksikan terhadap tubuh ? Bagaimana cara penanganan intoksikasi ? Dll

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44 TOXICOKINETICS (TOKSIKOKINETIK)
Studi pengaruh tubuh terhadap toksikan dan pergerakan toksikan didalam tubuh MTC Therapeutic MEC Ineffective

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46 Bioaccumulation = the accumulation of a contaminant or toxin in or on an organism from all sources (e.g., food, water, air). Biomagnification = the increase in concentration of toxin as it passes through successive levels of the food web

47 Assimilation Efficiency (= Lindeman’s Efficiency
Bioaccumulation Assimilation Efficiency (= Lindeman’s Efficiency Lindeman Ecology 23: ) AE increases with trophic level When a chemical is assimilated more efficiently than organic energy -> bioaccumulation AE

48 Scenario 1: Alewife (2o predator) eats Cercopagis 1o predator
Biomagnification Scenario 1: Alewife (2o predator) eats Cercopagis 1o predator cals. 1 10 100 ppm toxin 1 100 10,000 Scenario 2 cals. 1 100 ppm toxin 1000 1

49 Food Web Bioaccumulation

50 The Mercury Cycle

51 TOXICOKINETICS: Study of the time-course of toxins (study of what the body does to the toxin).

52 TOXICODYNAMICS (TOKSIKODINAMIK)
Studi efek pengaruh toksikan terhadap tubuh

53 TOXICODYNAMICS: Study of biochemical and physiological effects of drugs and toxins (study of what the toxin does to the body).

54 Target Organ Toxicity -Central Nervous System – lead
-Immune System - isocyanates -Liver - ethanol, acetaminophen -Respiratory Tract - tobacco smoke, asbestos, ozone -Eye - UV light (sunlight) -Kidney - metals -Skin - UV light, gold, nickel -Reproductive System –dibromochloropropane

55 Karakteristik Rute Pemaparan Toksikan (Exposure)
Rute dan Titik tangkap Pemaparan Ingestion (Gastrointestinal Tract) Inhalation (Lungs) Dermal/Topical (Skin) Injection intravenous, intramuscular, intraperitoneal Effectiveness pemaparan: iv > inhale > ip > im > ingest > topical

56 Dosis Jumlah bahan kimia / Toxicant yang memasuki tubuh Umumnya dalam satuan mg /kg BW Dosis Toxicant tergantung pada bbp faktor :  concentration di lingkungan sekitarnya  Karakteristik exposure  Lama exposure  Frekwensi exposure  Sifat toxicant

57 Toxicant Toxicant Toxicant

58 Passive diffusion MEKANISME TRANSPORT DARI TOXICANT Carrier-mediated
Active Facilitated ATP ADP-Pi Transporter Molecule

59 Memerlukan carrier Transport menjadi jenuh (saturated) pada konsentrasi tinggi Proses bersifat selective Dua obat yang ditranspor oleh mekanisme yg sama akan menghambat satu sama lain Melawan concentration gradient ( active transport) Tdk melawan cocentration gradient ( facilitated transport) Memerlukan energy Mekanisme transport dapat dihambat oleh obat obat yang mempengaruhi cellular metabolism Karakteristik facilitated diffusion dan active transport

60 Karakteristik dari molekul Un-ionized
Dan Ionized Toxicant Un-ionized Ionized Pharmacologic effect Active Inactive Solubility Lipids Water Cross lipid barriers Yes No (gastrointestinal tract, blood-brain barrier, placenta) Hepatic metabolism Yes No Renal excretion No Yes

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62 Absorption: Kemampuan bhn kimia memasuki darah (darah berkesimbangan dgn jaringan)
Inhalasi--gas menuju darah melalui alveoli. (luas permukaan alveolar, aliran darah banyak, lapisan antara darah menuju alveolar air) Ingestion--absorpsi melalui GI tract : stomach (asam), small intestine (contact time panjang, luas permukaan luas--villi; bases dan transporter bahan bahan tertentu) 1st Pass Effect (liver metabolism) Dermal—absorpsi melalui epidermis (stratum corneum), dermis; titik tangkap dan keadaan kulit

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64 Respiratory System Surface area approximately 50 to 100 m2 Nasopharynx
Oropharynx Epiglottis Thyroid cartilage Larynx Cricoid cartilage Trachea Bronchiole Left main bronchus Right main bronchus Bronchiole Diaphragm Lungs Alveolus Alveolar sac

65 Respiratory Physiology
CO 2 2 2 . CO 2 Blood from right side of heart Aveolus (low in O, 2 high in CO) O O 2 2 2 CO Blood to left CO 2 2 side of heart Reoxygenated blood (high in O, low in CO) Capillary 2 2 Red blood cells

66 Absorpsi Pulmonary Systemic (e.g. insulin, anesthetics)
dan local delivery Area absorpsi sangat luas Suplai darah sangat baik Tidak mengalami first pass effect Bentuk sediaan mahal Ukuran partikel : 2-5 m

67 Absorption from the Lungs
REMOVAL OF PARTICLES Absorption of Aerosols and Particles: 1- Particle Size 2- Water solubility of the chemical present in the aerosol or particle Lymph Physical Phagocytosis

68 Pemberian per inhalasi
Patikel > 10 um : diendapkan, dihembuskan dan berbangkis Partikel < 0.01 um : terbuang pada saat inspirasi dan ekspirasi Partikel 0.01 – 10 um :diendapkan pada alveoli, nasopharyng sampai bronchioli 25% dikeluarkan bersama udara nafas 50% diendapkan disalurannafas bagian atas 25% diendapkan disaluran nafas bagian bawah

69 Absorpsi dari Paru Gas, vapors,volatile liquids, aerosols and particles Large surface area, thin barrier, high blood flow rapid absorption Blood:air partition coefficient – dipengaruhi respiratory rate dan blood flow Blood:tissue partition coefficient

70 NasopharyngealRegion
DEPOSISI PARTIKEL TOKSIKAN DI DLM SALURAN RESPIRASI NasopharyngealRegion 5-30 µm Trachea Bronchi Bronchioles 1-5 µm Alveolar Region 1 µm

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72 Absorpsi dari kulit Melewati bbg lapisan sel (stratum corneum, epidermis, dermis) menuju pembuluh darah . Faktor yang mempengaruhi : lipid solubility, hydrasi kulit (sole of feet vs. scrotum)

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74 Absorption by the Skin

75 Absorpsi melalui kulit
Permeability depends on the diffusivity and thickness (depends on the area of the body) of the stratum corneum Polar  outer surface of protein filaments of the hydrated stratum corneum Nonpolar  lipid matrix between protein filaments Percutaneous absorption  lower layers of the epidermis and dermis Below the s.corneum  porous, nonselective aqueous medium Compromised stratum corneum integrity Increased stratum corneum hydration Increased temperature  increased blood flow Low solubility of toxicant in the vehicle Small size  Increased Absorption

76 Kecepatan distribusi Toxicant tergantung : -- aliran darah
Distribution: proses translokasi dari Toxicant menuju seluruh bagian tubuh Darah membawa Toxicant menuju site of action, storage depots, organ transformasi, dan organ eliminasi Kecepatan distribusi Toxicant tergantung : -- aliran darah karakteristik toxicant (afinitas thd jaringan dan partition coefficient) Distribusi mungkin berubah setiap waktu

77 Distribusi: Storage / Binding
Storage di dlm Adipose tissue  sangat lipophylic (DDT). Cepat dimobilisasi dari fat (starvation) , cepat meningkat dalam darah cepat meningkat dalam darah Storage dalam tulang (Bone)  Chemicals analog dgn Calcium--Fluoride, Lead, Strontium Ikatan dgn Plasma proteins  mendesak senyawa endogenous . Hanya fraksi bebas  adverse effects dan excretion

78 Metabolism: Toxicant lebih water soluble (Polar)  ekskresi
Menurunkan lipid solubility  menurunkan jumlah toxicant pada target Meningkatkan ionisasi  meningkatkan excretion rate --> menurunkan toxicity Bioactivasi  Biotransformasi  pembentukan reactive metabolites

79 Biotransformation (Metabolism)
Meningkatkan kec clearance dari toxicant Dapat terjadi mulai absorpsi  ekskreri

80 Biotransformation Key organs in biotransformation
LIVER (high) Lung, Kidney, Intestine (medium) Others (low) Biotransformation Pathways Phase I--make the toxicant more water soluble Phase II--Links with a soluble endogenous agent (conjugation)

81 FPE Beberapa toxin tidak efektif bila digunakan peroral (snake venome)
Bila toxicant dimetabolisme menjadi bentuk aktif (ultimate toxicant)  kumulatif dari metabolit toxic

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84 Distribution: the process in which a chemical agent translocates throughout the body
Blood carries the agent to and from its site of action, storage depots, organs of transformation, and organs of elimination Rate of distribution (rapid) dependent upon blood flow characteristics of toxicant (affinity for the tissue, and the partition coefficient) Distribution may change over time

85 Distribution: Storage and Binding
Storage in Adipose tissue--Very lipophylic compounds (DDT) will store in fat. Rapid mobilization of the fat (starvation) can rapidly increase blood concentration Storage in Bone--Chemicals analogous to Calcium--Fluoride, Lead, Strontium Binding to Plasma proteins--can displace endogenous compounds. Only free is available for adverse effects or excretion

86 Target Organs: adverse effect is dependent upon the concentration of active compound at the target site for enough time Not all organs are affected equally greater susceptibility of the target organ higher concentration of active compound Liver--high blood flow, oxidative reactions Kidney--high blood flow, concentrates chemicals Lung--high blood flow, site of exposure Neurons--oxygen dependent, irreversible damage Myocardium--oxygen dependent Bone marrow, intestinal mucosa--rapid divide

87 Target organ Carbon tetrachloride – liver Mercury & lead – CNS, kidneys & hematopoietic system Benzene – hematopoietic system Storage sites Dichlorodiphenyltrichloroethane (DDT) – fat depots  no toxic effect

88 Lungs are capable of biotransformation & elimination
Nose is a “scrubber” for water-soluble and highly reactive gases Solubility ratio (blood-to-gas partition coefficient) – conc. in blood/conc. in gas phase before or at saturation Low solubility ratio – blood flow through the lungs (perfusion-limited) Highs solubility ratio – rate and depth of respiration (ventilation-limited) Lungs are capable of biotransformation & elimination Steady state concentration can be reached Aerosols  dependent on aerosol size & water solubility 5um or more – lodged in nasopharyngeal region 2.5 um – tracheobronchial region 1 um or less – alveolar sacs of blood

89 Efek Toxic Berdasarkan Mekanisme
Allergic (hypersensitivity,Antigen) Idiosyncratic (e.g. G6PD def., Drugs) Local vs. Systemic (Corrosive agent) Reversible vs. Irreversible Necrosis /organ damage (Ozone, Lead, Cd, Sr) Carcinogenecity (Benzene, Rokok, Asbestos, Coloring Agent) Mutagenicity (uv light, Coloring Agent) Teratogenicity (Drugs:Thalidomide, Valproic acid, Herbal) Death (Arsen, Cyanide) 89

90 Efek Toksik Berdasarkan Lama Pemaparan (Exposure)
Acute toxicity < 24hr umumnya 1 x paparan Subacute toxicity bulan dosis berulang Subchronic toxicity 1-3 bulan dosis berulang Chronic toxicity > 3 bulan dosis berulang Pada pemakaian berulang  akumulasi Toxicant didalam tubuh

91 Sifat Toxicant Acute Toxicity
Biasanya menyebabkan kematian Th 1989, 5,000 orang meninggal dan 30,000 cacat permanen akibat terpapar methyl isocyanate akibat kebocoran industri di India. Subchronic Toxicity - Minum coumadin tablets (blood thinners) beberapa minggu pada pengobatan venous thrombosis menyebabkan perdarahan internal . Chronic Toxicity - cirrhosis pada alcoholics (beberapa tahun) - chronic kidney disease pada pekerja terpapar Pb beberapa tahun - chronic bronchitis pada cigarette smokers - pulmonary fibrosis pada pekerja tambang (black lung disease) - Carcinogenicity, Mutagenicity - Developmental Toxicity, Teratogenicity Embryolethality,embryotoxic,teratogenic - Genetic Toxicity (somatic cells) Gene mutation,chromosome aberration,aneuploidy,polyploidy

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93 Target Organs: adverse effect tergantung pada kadar senyawa aktif dlm target site untuk waktu yang cukup Tidak semua organ dipengaruhi sama ,tetapi tergantung Kepekaan target organ Kadar toxicant yg tinggi dalam target organ Liver—aliran drh sangat tinggi,oxidative reactions Kidney—aliran drh sangat tinggi, bhn kimia terkonsentrat Lung--high blood flow, tempat pemaparan Neurons--oxygen dependent, kerusakan irreversible Myocardium--oxygen dependent Bone marrow, intestinal mucosa -- rapid divide cell

94 Target Sites: Mechanisms of Action
Adverse effects can occur at the level of the molecule, cell, organ, or organism Molecularly, chemical can interact with Proteins Lipids DNA Cellularly, chemical can interfere with receptor-ligand binding interfere with membrane function interfere with cellular energy production bind to biomolecules perturb homeostasis (Ca)

95 Excretion: Toxicants are eliminated from the body by several routes
Urinary excretion water soluble products are filtered out of the blood by the kidney and excreted into the urine Exhalation Volatile compounds are exhaled by breathing Biliary Excretion via Fecal Excretion Compounds can be extracted by the liver and excreted into the bile. The bile drains into the small intestine and is eliminated in the feces. Milk Sweat Saliva Excretion: Toxicants are eliminated from the body by several routes

96 Mekanisme kerusakan sel (cellular injury)
Perubahan permeabilitas cell membrane Perubahan enzymes activity. Modifikasi carriers. Reaksi yg menyebabkan deplesi GSH. Interaksi dgn co-enzyme. Interaksi dgn nucleic acid. Pembentukan reactive metabolite. Perubahan protein synthesis. Immunotoxicity. Perubahan Lysosomal Inhibisi cellular respiration.

97 Occupancy Theory T + R T-R Complex Response

98 Law of Mass Action R + T RT [R].[T].kf [RT].kb Kec. asosiasi = [R].[T].kf Kec. disosiasi = [RT].kb Pada keseimbangan  [R].[T].kf = [RT].kb Keduanya dibagi dengan kf [R].[T]=[RT].kb/kf (1)

99 Let Kd = kb/kf [R].[T]=[RT].Kd (2)
[Rt] = total no. receptors [Rt] = [R] + [RT] Subst [R] = [Rt]-[RT] ke (2) [T]([Rt]-[RT]) = [RT].Kd Selanjutnya [RT](Kd+[T]) = [T].[Rt] Dibagi dengan [Rt] [RD](Kd+[T])/[Rt] = [T] Dibagi oleh (Kd + [T]) [RT] = [T] [Rt] [T] + Kd Besarnya efek toksik sebanding dengan komplek TR yaitu E ~ [TR] Respon maximum terjadi bila semua reseptor diduduki toksikan, yaitu Emax ~ [Rt] Fraksi reseptor yang diduduki toxicant = efek = respon = RT / Rt

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101 Model dari “Occupancy Theory”
Toxicant

102 Dose Response Relationship
All Effected 100 80 75 % Response 50 Half Effected 25 NO Adverse Effect level 20 10 20 30 40 50 60 70 80 90 100 Dose (mg/kg body weight) Increasing dose

103 Dose-response relationship: LEAD (Pb)
decreased erythrocyte delta-ALAD activity increased zinc protoporphyrin anemia CNS effects decreased peripheral nerve conductivity Nervous paralysis, lead colics Adapted from Elinder C-G et al., Biologisk monitoring av metaller hos människa. Arbetsmiljöfonden, Uppsala, 1991

104

105

106 Maximum Effect atau Efficacy
Kurva Dosis-Efek ( in vivo) Maximum Effect atau Efficacy Slope Effect Potency Log Dose

107 Kurva Dose - Respon in vivo ( Efficacy & Potency )

108 Perbedaan Potensi Dose Dioxine Rattle snake Strychnine Sulfate
100 Strychnine Sulfate Ethyl Alcohol % of Lethality 50 LD50 Dose

109 Hubungan Dosis-Efek : Phenobarbital
Therapeutic Index: LD50 ED50 Hipnotik Mati % Respon ED50 LD50 Dosis Phenobarbital

110 Toxicity Studies Acute Toxicity
LD 50,Max Tolerated Dose,2 species,2 route, single dose Subacute Toxicity 3 doses,2 doses, 4 weeks-3 months, Chronic Toxicity Rodent,non-rodent, 6 months and more Effect on reproductive performance Effects on animal mating behavior,reproduction,parturition,progeny,birth defects,postnatal development Carcinogenic potential 2 years, 2 species Mutagenic potential Effects on genetic stability and mutations in bacteria (Ames test) or mammalian cells in culture, dominant lethal test and clastogenicity in mice Investigative Toxicology Determine sequence and mechanisms of toxic action, etc

111 Qualitative Observation
Body Weight and Food Consumption Ophthalmology interval Hematology parameters Clinical Chemistry Parameters Urinalysis Parameters Organ Weight Microscopic Pathology Animal Responses  Clinical Signs of Toxicity  Autonomic Signs Etc CRC Handbook of Toxicology,2005

112 Quantitative Observation
Acute Toxicity  ED-50, LD-50, TI Sub Chronic and Chronic Toxicity  ADI, NOEL, NOAEL CRC Handbook of Toxicology,2005

113 Acute Toxicity - Acute toxicity dilakukan pertama kalinya (biasanya oral dan IV) - Menentuklan harga LD Binatang coba mati dlm waktu 7-14 hari period after a single dose is tabulated. - Tanda tanda intoksikasi, lethargy, perubahan perilaku, studi biokimia harus dilakukan

114 (short-term exposure)
Acute Toxicity: (short-term exposure) 114

115 LD50 Quantal responses dihitung bila data dari populasi. Bila mortality berupa response, maka dosis pada 50% dari populasi  LD50 LD 50 paling kecil  paling toxic Therapeutic Index (TI) is the ratio of the dose required to produce a toxic effect to that required to produce a desired therapeutic response(LD50/ED50)

116 LD50 berbagai bahan kimia
Toxicant LD50 (mg/kg) Ethyl alcohol 10,000 Salt (sodium chloride) 4,000 Iron (Ferrous sulfate) 1,500 Morphine Mothballs (paradichlorobenzene) 500 Aspirin DDT Cyanide 10 Nicotine 1 Black Widow Spider venom 0.55 Rattle Snake venom Tetrodotoxin (from fish) 0.01 Dioxin (TCDD) Botulinum Toxin

117 Subchronic toxicity tests
Uji toksisitas selama 90 hari Dua species (rats dan dogs) 3 dosis level Tiap dosis minimum 15 binatang (jantan/betina) Pengamatan : Mortality, body weight, diet consumption, hematology dan clinical chemistry. Pemeriksaan Gross dan microscopic dari tiap organs dan jaringan.

118 Long term / chronic exposure studies
Dilakukan mirip dengan pengamatan pada studi sub chronic, kecuali dengan periode lebih lama . Mis, uji toksisitas Antimicrobial agents dan food additives. Terutama penentuan carcinogenic potential Dilakukan pada tikus, mice, spesies lainnya selama life spent (masa hidup) dari tiap spesies

119 Chronic Toxicity: (repeated exposures) 119

120 Dose levels (animal studies)
NOEL no-observed effect level NOAEL no-observed-adverse effect level LOAEL lowest-observed-adverse effect level MTD maximum tolerated dose LD dose which kills 50% of population LC concentration which kills 50% of population; must include time frame Increasing dose 120

121

122

123 Toxicity Rating Chart (Casarett & Doulls)
Clasification Probable lethal oral dose for humans Dosage For average adult Toxicity rating/ Class Practically non toxic > 15 g/kg More than 1 quart Slightly toxic 5 – 15 g/kg Between pint and quart Moderately toxic 0.5 – 5 g/kg Between ounce and quart Very toxic 50 – 500 mg/kg Between teaspoonful and ounce Extremely toxic 5 – 50 mg/kg Between 7 drops and teaspoonful Supertoxic < 5 mg/kg A taste (less than 7 drops)

124 Uji Dermal dan Ocular - Uji Dermal biasanya umumnya dilakukan pada kelinci. Chemical toxicant dikenakan pada kulit dean dibiarkan kontak selama jam. - Iritasi kulit ditandai dengan adanya erythema scar, pembentukan edema, sifat corrosive - Pada Ocular test, toxicant diteteskan pada satu mata dan lainnya sebagai kontrol pada kelinci Perubahan pada mata diamati pada beberapa interval ttt

125

126 Qualitative Observation
Body Weight and Food Consumption Ophthalmology interval Hematology parameters Clinical Chemistry Parameters Urinalysis Parameters Organ Weight Microscopic Pathology Animal Responses  Clinical Signs of Toxicity  Autonomic Signs Etc CRC Handbook of Toxicology,2005

127

128 Toxicity rating Toxicity rating or class Dosage for average adult
Probable lethal oral dose for human Dosage for average adult 1. Practically nontoxic > 15 g/kg more than 1 quart (>0.94 L) 2. Slightly toxic 5-15 g/kg between pint and quart ( L) 3. Moderately toxic 0.5-5 g/kg between ounce and pint (28 mL-0.47L) 4. Very toxic mg/kg between teaspoon and ounce (5-28 mL) 5. Extremely toxic 5-50 mg/kg between 7 drops and teaspoon 6. Supertoxic < 5 mg/kg a taste (less than 7 drops) 128